Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study - 2020 - Rekeland, Mella, Fluge et al

Kalliope

Kalliope

Senior Member (Voting Rights)
published in frontiers in Medicine - Family Medicine and Primary Care

Results: The overall response rate by Fatigue score was 55.0% (22 of 40 patients). Fatigue score and other outcome variables showed significant improvements compared to baseline. The SF-36 Physical Function score increased from mean 33.0 at baseline to 51.5 at 18 months (all patients), and from mean 35.0 to 69.5 among responders. Mean steps per 24 h increased from mean 3,199 at baseline to 4,347 at 18 months (all patients), and from 3,622 to 5,589 among responders. At extended follow-up to 4 years 68% (15 of 22 responders) were still in remission. Patients positive for HLA-DQB1*03:03 and/or HLA-C*07:04 (n = 12) had significantly higher response rate compared to patients negative for these alleles (n = 28), 83 vs. 43%, respectively. Nausea and constipation were common grade 1–2 adverse events. There were one suspected unexpected serious adverse reaction (aggravated POTS) and 11 serious adverse events in eight patients.

Conclusion
This study shows that cyclophosphamide intervention is feasible for ME/CFS patients. The growing evidence for immune alterations in ME/CFS and the high symptom burden with very low quality of life, we believe can justify use of an immune modulating drug with possible side effects. The treatment period was demanding for most patients, but in total the toxicity was interpreted as acceptable. The treatment was associated with long-lasting improvements of ME/CFS symptoms for approximately half of patients. However, due to the lack of a placebo group, response data must be interpreted with great caution. In the further work to find effective treatment, we will consider a new multicenter, randomized, double-blind and placebo-controlled trial with cyclophosphamide. Should this trial prove cyclophosphamide to be beneficial for ME/CFS patients, this could also be important in the search for relevant disease mechanisms.

https://www.frontiersin.org/articles/10.3389/fmed.2020.00162/full

Edit: swapped conclusion from the abstract to the conclusion in the main text as it was more supplementary
 
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Merged thread

Ingrid G. Rekeland 1, Alexander Fosså 2, Asgeir Lande 3, Irini Ktoridou-Valen 1, Kari Sørland 1, Mari Holsen 4, Karl J. Tronstad 5, Kristin Risa 1, Kine Alme 1, Marte K. Viken 3,6, Benedicte A. Lie 3,6, Olav Dahl 5, Olav Mella 1,5 and Øystein Fluge 1,5*
  • 1 Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
  • 2 Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
  • 3 Department of Medical Genetics, Oslo University Hospital and Faculty of Medicine, University of Oslo, Oslo, Norway
  • 4 Clinical Research Unit, Haukeland University Hospital, Bergen, Norway
  • 5 Department of Biomedicine, University of Bergen, Bergen, Norway
  • 6 Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway
Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with high symptom burden, of unknown etiology, with no established treatment. We observed patients with long-standing ME/CFS who got cancer, and who reported improvement of ME/CFS symptoms after chemotherapy including cyclophosphamide, forming the basis for this prospective trial.

Materials and methods: This open-label phase II trial included 40 patients with ME/CFS diagnosed by Canadian criteria. Treatment consisted of six intravenous infusions of cyclophosphamide, 600–700 mg/m2, given at four-week intervals with follow-up for 18 months, extended to 4 years. Response was defined by self-reported improvements in symptoms by Fatigue score, supported by Short Form 36 (SF-36) scores, physical activity measures and other instruments. Repeated measures of outcome variables were assessed by General linear models. Responses were correlated with specific Human Leukocyte Antigen (HLA) alleles.

Results: The overall response rate by Fatigue score was 55.0% (22 of 40 patients). Fatigue score and other outcome variables showed significant improvements compared to baseline. The SF-36 Physical Function score increased from mean 33.0 at baseline to 51.5 at 18 months (all patients), and from mean 35.0 to 69.5 among responders. Mean steps per 24 h increased from mean 3,199 at baseline to 4,347 at 18 months (all patients), and from 3,622 to 5,589 among responders. At extended follow-up to 4 years 68% (15 of 22 responders) were still in remission. Patients positive for HLA-DQB1*03:03 and/or HLA-C*07:04 (n = 12) had significantly higher response rate compared to patients negative for these alleles (n = 28), 83 vs. 43%, respectively. Nausea and constipation were common grade 1–2 adverse events. There were one suspected unexpected serious adverse reaction (aggravated POTS) and 11 serious adverse events in eight patients.

Conclusion: Intravenous cyclophosphamide treatment was feasible for ME/CFS patients and associated with an acceptable toxicity profile. More than half of the patients responded and with prolonged follow-up, a considerable proportion of patients reported ongoing remission. Without a placebo group, clinical response data must be interpreted with caution. We nevertheless believe a future randomized trial is warranted.

Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02444091.

Link: https://www.frontiersin.org/articles/10.3389/fmed.2020.00162/full
 
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"This study shows that cyclophosphamide intervention is feasible for ME/CFS patients. The growing evidence for immune alterations in ME/CFS and the high symptom burden with very low quality of life, we believe can justify use of an immune modulating drug with possible side effects. The treatment period was demanding for most patients, but in total the toxicity was interpreted as acceptable."
 
“Mean steps per 24 h increased from mean 3,199 at baseline to 4,347 at 18 months (all patients), and from 3,622 to 5,589 among responders.”

Is this mild ME, the patients on the trial?

There are also lots of adverse effects (11 out of 40). I don’t think those with severe ME, or with medication sensitivity, would be able to tolerate many side effects.

but the fact those who responded had those specific alleles is really interesting. Are these the same alleles that Simon M recently reported on?
 
Interesting. Would be it overly optimistic to say that despite the open label nature of the trial, they succeeded in producing some evidence that immunosuppression is helpful for a subset? Not definitive evidence but enough to say that this line of investigation is not a dead end?

Edit:

Second question. If immunosuppression is helping, what is being suppressed? Considering that B cell depletion does not seem to work. Presumably that means it's T cells. Are there other possibilities?
 
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This seems pretty interesting, especially with the 70% still in remission after 4 years. I guess we should keep in mind that the unblinded Ritux trial has let us down before though.

cassava7 said:
The SF-36 Physical Function score increased from mean 33.0 at baseline to 51.5 at 18 months (all patients), and from mean 35.0 to 69.5 among responders.
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Isn't this a pretty high baseline for pwME in general? Iirc 'we' should score roughly half that, but maybe I am mistaken. I guess it makes sense to test on the most robust patients in a way with a drug as harsh as this, but who knows if it is feasible to extrapolate to more severe patients then. As far as I am aware, a score of 70 and below is actually still pretty miserable compared to a healthy person (although obviously a far cry from what life is in the sub40s).

Does anybody know when bladder cancer would usually become apparent with the dosages used? The serious adverse events listed aren't really that bad and don't really sound like permanent worsening apart from the one POTS-incident.

Also, if this is no fluke and some of the cells the cyclo kills are really key to maintaining ME - shouldn't there already be a -mab biologic somewhere or at least down the line that would be worth trying with possibly less side effects or am I overly optimistic?
 
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This is the whole Discussion section (my bolding),

"This study shows that cyclophosphamide intervention is feasible for ME/CFS patients. The growing evidence for immune alterations in ME/CFS and the high symptom burden with very low quality of life, we believe can justify use of an immune modulating drug with possible side effects. The treatment period was demanding for most patients, but in total the toxicity was interpreted as acceptable. The treatment was associated with long-lasting improvements of ME/CFS symptoms for approximately half of patients. However, due to the lack of a placebo group, response data must be interpreted with great caution. In the further work to find effective treatment, we will consider a new multicenter, randomized, double-blind and placebo-controlled trial with cyclophosphamide. Should this trial prove cyclophosphamide to be beneficial for ME/CFS patients, this could also be important in the search for relevant disease mechanisms."

And below is all my own opinion.

We have been here before with rituximab, where pwME have sought treatment based on positive early stage trials, only to have their health irreparably harmed, their bank balance severely reduced, and for it to turn out that actually rituximab wasn't the treatment that we hoped it would be anyway. I completely understand why they would have, and empathise with the desire to be better, but I would urge everybody not to now go seek treatment with cyclophosphamide - we need to wait for a full stage 3 trial to be performed before deciding whether or not to have cyclophosphamide.

I mean that as no slight aimed at patients or Fluge, Mella and the rest of their team, merely as a note of caution for all the desperate people out there.
 
shak8 said:
I haven't read the article carefully enough yet.

But since fatigue itself is a symptom of cancer before diagnosis in many instances (=cancer-related fatigue at baseline + ME/CFS exhaustion), might the infusions of cyclophosphamide decrease the fatigue resulting from cancer (recorded at various intervals and at termination of follow-up) rather than the effect of the drug on ME/CFS exhaustion or at least confound the result?
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The subjects in this study were pwME, not cancer patients.

Inclusion criteria were: a diagnosis of ME/CFS according to the Canadian criteria (4); age 18–66 years; disease duration more than 2 years; and disease severity mild-to-moderate, moderate, moderate-to-severe, or severe. Patients with either mild or very severe disease (completely bedbound and in need of help for all basic activities of daily living) were not included. The exclusion criteria and pre-treatment evaluation are detailed in the trial protocol (Data Sheet 1).
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Philipp said:
Does anybody know when bladder cancer would usually become apparent with the dosages used? The serious adverse events listed aren't really that bad and don't really sound like permanent worsening apart from the one POTS-incident.
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Yes. Bladder cancer can occur at any time over the next fifty years. Any bladder cancers arising from this trial are very unlikely to have shown up yet. Rates for regimens used these days are not the 40% that occurred in early studies prior to 1980 but the risk is till there.

I was involved in cyclophosphamide usage for autoimmune disease over a period of decades, including my own trials. At the end I concluded that I would never use cyclophosphamide in non-malignant disease unless there was an acute risk of death in the near future and no other treatments were available. I have huge respect for Fluge and Mella but I cannot see cyclophosphamide being an acceptable treatment for ME.

Apart from the cancer issue most people find taking it pretty unpleasant.
 
Andy said:
This is the whole Discussion section (my bolding),

"This study shows that cyclophosphamide intervention is feasible for ME/CFS patients. The growing evidence for immune alterations in ME/CFS and the high symptom burden with very low quality of life, we believe can justify use of an immune modulating drug with possible side effects. The treatment period was demanding for most patients, but in total the toxicity was interpreted as acceptable. The treatment was associated with long-lasting improvements of ME/CFS symptoms for approximately half of patients. However, due to the lack of a placebo group, response data must be interpreted with great caution. In the further work to find effective treatment, we will consider a new multicenter, randomized, double-blind and placebo-controlled trial with cyclophosphamide. Should this trial prove cyclophosphamide to be beneficial for ME/CFS patients, this could also be important in the search for relevant disease mechanisms."

And below is all my own opinion.

We have been here before with rituximab, where pwME have sought treatment based on positive early stage trials, only to have their health irreparably harmed, their bank balance severely reduced, and for it to turn out that actually rituximab wasn't the treatment that we hoped it would be anyway. I completely understand why they would have, and empathise with the desire to be better, but I would urge everybody not to now go seek treatment with cyclophosphamide - we need to wait for a full stage 3 trial to be performed before deciding whether or not to have cyclophosphamide.

I mean that as no slight aimed at patients or Fluge, Mella and the rest of their team, merely as a note of caution for all the desperate people out there.
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Very important point, @Andy and it seems that the researchers agree with you completely as they write:
We strongly advise patients and physicians not to use cyclophosphamide for ME/CFS patients outside of clinical trials before a randomized trial has been conducted, to evaluate the possible benefits of the drug.
 
I dont have the energy to do this but someone else might:
Would it be possible to make a direct comparison of the outcome data from this trial with the same stage Rituximab trial, and also with the control group from the final double blinded Rituximab trial? I don't remember whether the same outcome measures were used, but I do recall there was a surprisingly high 'recovery' rate in the blinded placebo group.
 
What @Trish suggested sounds like a really good idea to me. I hope someone is up to that!

Jonathan Edwards said:
I have huge respect for Fluge and Mella but I cannot see cyclophosphamide being an acceptable treatment for ME.

Apart from the cancer issue most people find taking it pretty unpleasant.
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Thank you again for your insight! It is quite frankly really good to be able to rely on you all the time...

I personally would really not care if it made me vomit for an entire week after taking it (..assuming no lasting damage from that and not dying of dehydration or somesuch) if I could literally double my capacity for half a decade after going through a horrible half-year period and I possibly would do that again for the rest of my life if that was all it took. ME is... not pleasant. But I am still pretty young-ish all things considered and death is usually so... permanent. So I do hope this leads to some idea of a less harsh treatment down the line and we don't get another disappointment if there ever is a proper blinded trial.
 
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Jonathan Edwards said:
Yes. Bladder cancer can occur at any time over the next fifty years. Any bladder cancers arising from this trial are very unlikely to have shown up yet. Rates for regimens used these days are not the 40% that occurred in early studies prior to 1980 but the risk is till there.

I was involved in cyclophosphamide usage for autoimmune disease over a period of decades, including my own trials. At the end I concluded that I would never use cyclophosphamide in non-malignant disease unless there was an acute risk of death in the near future and no other treatments were available. I have huge respect for Fluge and Mella but I cannot see cyclophosphamide being an acceptable treatment for ME.

Apart from the cancer issue most people find taking it pretty unpleasant.
Click to expand...

What long term concerns did u find occur other than bladder cancer in ur practice?
 
Philipp said:
70% still in remission after 4 years.
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To clarify: I suspect the figure of 70% you use refers to the 68% reported in the paper. But this was 68% of the 22 patients who already responded to the treatment. If you compare it to the total number of patients in the trial it's only 38% (and that's a figure without a control group).

I hope everyone will report the results of this trial extra carefully on social media and patient groups. It's an interesting study, but there was no control group and there were serious side effects (there were 11 serious adverse events that resulted in hospitalization). As noted by Kalliope, the authors write (my bolding)
We strongly advise patients and physicians not to use cyclophosphamide for ME/CFS patients outside of clinical trials before a randomized trial has been conducted, to evaluate the possible benefits of the drug
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